Correspondence

8. Choi YL, Soda M, Yamashita Y, et al: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734-1739, 2010 9. ClinicalTrials.gov: An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specic Gene Prole Involving The Anaplastic Lymphoma Kinase (ALK) Gene. http:// clinicaltrials.gov/ct2/show/NCT00932893?term NCT00932893&rank 1

10. Simon G, Sharma A, Li X, et al: Feasibility and efcacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 25:2741-2746, 2007

DOI: 10.1200/JCO.2011.35.4605; published online ahead of print at www.jco.org on July 18, 2011

Is It Pre-Enucleation Chemotherapy or Delayed Enucleation of Severely Involved Eyes With Intraocular Retinoblastoma That Risks Extraocular Dissemination and Death?
TO THE EDITOR: As representatives from cooperative groups who treat retinoblastoma with prospective clinical trials that include use of pre-enucleation chemotherapy in countries with varying resources, we wish to comment on the article by Zhao et al1 entitled, Pre-Enucleation Chemotherapy for Eyes Severely Affected by Retinoblastoma Masks Risk of Tumor Extension and Increases Death From Metastasis. We believe that this strong statement against pre-enucleation chemotherapy might be potentially misleading for treating physicians, especially in less developed countries, who might interpret from it that initial enucleation should be attempted in all patients with advanced retinoblastoma, including those with different degrees of orbital dissemination. Therefore, we wish to emphasize, as a consensus statement, that initialenucleationisthetreatmentofchoiceforgroupEandmostgroupD eyes with intraocular retinoblastoma. However, there are instances when initial enucleation of severely affected eyes is not recommended. The decision to use enucleation should be made after a careful clinical staging that includes, when available, high-resolution magnetic resonance imaging (MRI) to rule out dissemination to the orbit, including the optic nerve.2,3 In our treatment protocols, pre-enucleation (neoadjuvant) chemotherapy followed by planned enucleation and intensive adjuvant chemotherapy and orbital radiotherapy, when microscopical disease is left behind in the orbit, is the treatment of choice for patients with clinicoradiologic evidence of extraocular disease or severe buphthalmia.4-7 On occasion, orbital dissemination is obvious from clinical examination, but in some patients it is only evident after a careful imaging work-up. For these patients, preoperative imaging methods especially high resolution MRI are useful to show extraocular extension, particularly within the optic nerve.2,3 This approach avoids orbital exenteration, which is a useless and mutilating surgery, in most children with massive orbital extension,6 and may decrease the risk of leaving a tumor remnant in the resection margin of the optic nerve,8 allowing for effective systemic therapy to be begun immediately after diagnosis. Prompt systemic treatment is important in these high-risk children in whom a rapidly growing tumor may lead to CNS or systemic dissemination; at the same time, it provides tumor chemoreduction for the fellow eye in situations of bilateral disease. The response to chemotherapy is usually dramatic and allows for limited surgery after two to four cycles of treatment.5,6 Our groups support the use of intensive adjuvant therapy after secondary enucleation, and we do not recommend therapy de-escalation, even when the pathology examination shows no risk factors, and even in patients
www.jco.org

with chemotherapy-induced complete necrosis of the tumor. A lowintensity adjuvant treatment that omitted orbital radiotherapy might have also been a factor for mortality in the series that was described by Zhao et al.1 Ourapproachhasshownsurvivalratesintherangeof70%to80%in patients with orbital dissemination6,9; these rates compare favorably with historical series using initial surgery followed by conventional chemotherapy and radiotherapy.10 Pre-enucleation chemotherapy was also reported for children with intraocular disease but with severe buphthalmia.8 These children have a signicantly higher risk of presenting with tumors at the resection margin of the optic nerve, which is correlated with the highest risk of extraocular relapse, or globe rupture if initial enucleation is performed.11 In this population, the use of pre-enucleation chemotherapy is under evaluation in prospective protocols by some of our treating groups with the aim of causing tumor regression, thereby making enucleation safer, potentially avoiding ocular perforation, and allowing the surgeon to obtain a longer optic nerve stump, which may result in a complete resection of the tumor. However, in some less developed countries, many families opt out of recommended initial enucleation for their children, and the management of these patients represents a challenge for the treating group.12 In these situations, a comprehensive, culture-sensitive approach should be pursued to convince the families to accept enucleation. The use of preenucleation chemotherapy, as described by Zhao et al,1 may help in providingtimeforthesefamiliestoaccepttheprocedure.Weproposethat itispossiblethatdelayedenucleationafterprolongedchemotherapytreatment was the major determinant of relapse in the series reported by Zhao et al. Given that three of four of their patients who relapsed had tumor invasion to the resection margin of the optic nerve or extrascleral invasion (the highest score for risk assessment on the basis of pathology risk factors),itisunlikelythatthemajorcauseofincreasedmortalityintheirseries was the use of preoperative chemotherapy that masked the tumor extension, as stated by the authors in the title of the article. If pre-enucleation chemotherapy indeed masked histologic features of extraocular extension, patients who relapsed should have had low-risk pathology features that misled the treating physicians in the estimation of relapse risk at the time of determining postenucleation therapy. Although no data from clinical staging that is designed for the assessment of extraocular disease (such as the International Retinoblastoma Staging System, the clinical TNM, the Grabowski-Abramson, or the St Jude Staging System) were provided in their report, these patients had apparently no imaging evidence of extraocular extension according to the available imaging studies (B. Gallie, personal communication, April 2011). However, highresolution MRI was not available in their center. Therefore, an alternative explanation for the occurrence of relapse in the patients who received pre-enucleation chemotherapy could be that extraocular disease developed under treatment and disease progression occurred because of delay in enucleation, despite the use of chemotherapy. As in other pediatric solid tumors, timely local control of the primary tumorin this malignancy, preferably by surgeryis
2011 by American Society of Clinical Oncology

3333

Downloaded from jco.ascopubs.org on May 14, 2012. For personal use only. No other uses without permission. Copyright 2011 American Society of Clinical Oncology. All rights reserved.

Correspondence

critical to avoid disease progression that results from chemotherapy resistance, and a delay in implementing this phase might have been the most signicant factor that led to relapse. Therefore, we concur with the conclusion of Zhao et al1 that enucleation should not be delayed in patients with group D or E eyes in whom preoperative extent of disease evaluation fails to show evidence of extraocular extension. However, we believe that pre-enucleation chemotherapy is the treatment of choice for children with clinical or radiologic evidence of orbital disease and possibly for those with massive buphthalmia. If preoperative chemotherapy needs to be administered because families decline enucleation for their children, it should be restricted to one to two cycles, with the sole aim of providing time for the family and thetreatinggrouptonegotiateandaccepttheconceptofenucleation.This is a valid option for families who reject initial enucleation and whose children would die of disseminated disease if they received no treatment.12,13 In these situations, the value of pathology risk factors to predict theriskofextraocularrelapseaftersecondaryenucleationmaybemisleading, and adjuvant therapy de-escalation that is based on pathology results may not be safe. Additional study would be necessary to generate guidelines for adjuvant therapy in this population.

Nurdan Tacyildiz
Ankara University Retinoblastoma Group; Ankara University, School of Medicine, Ankara, Turkey

Sandra Luna Fineman

Asociacion de Hemato-Oncologia Pediatrica de Centro America; Stanford University, Palo Alto, CA

Livia Lumbroso and Francois Doz

Institut Curie Paris and University Paris Descartes, Paris, France

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conicts of interest.

REFERENCES
1. Zhao J, Dimaras H, Massey C, et al: Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. J Clin Oncol 29:845-851, 2011 2. Brisse HJ, Guesmi M, Aerts I, et al: Relevance of CT and MRI in retinoblastoma for the diagnosis of postlaminar invasion with normal-size optic nerve: A retrospective study of 150 patients with histological comparison. Pediatr Radiol 37:649-656, 2007 3. de Graaf P, Barkhof F, Moll AC, et al: Retinoblastoma: MR imaging parameters in detection of tumor extent. Radiology 235:197-207, 2005 4. Antoneli CB, Steinhorst F, de Cassia Braga Ribeiro K, et al: Extraocular retinoblastoma: A 13-year experience. Cancer 98:1292-1298, 2003 5. Doz F, Khelfaoui F, Mosseri V, et al: The role of chemotherapy in orbital involvement of retinoblastoma: The experience of a single institution with 33 patients. Cancer 74:722-732, 1994 6. Chantada G, Fandino A, Casak S, et al: Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol 40:158-161, 2003 7. Leal-Leal CA, Rivera-Luna R, Flores-Rojo M, et al: Survival in extra-orbital metastatic retinoblastoma: Treatment results. Clin Transl Oncol 8:39-44, 2006 8. Bellaton E, Bertozzi AI, Behar C, et al: Neoadjuvant chemotherapy for extensive unilateral retinoblastoma. Br J Ophthalmol 87:327-329, 2003 9. Antoneli CB, Ribeiro KB, Rodriguez-Galindo C, et al: The addition of ifosfamide/ etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement. J Pediatr Hematol Oncol 29:700-704, 2007 10. Goble RR, McKenzie J, Kingston JE, et al: Orbital recurrence of retinoblastoma successfully treated by combined therapy. Br J Ophthalmol 74:97-98, 1990 11. Chantada GL, Gonzalez A, Fandino A, et al: Some clinical ndings at presentation can predict high-risk pathology features in unilateral retinoblastoma. J Pediatr Hematol Oncol 31:325-329, 2009 12. Sitorus RS, Moll AC, Suhardjono S, et al: The effect of therapy refusal against medical advice in retinoblastoma patients in a setting where treatment delays are common. Ophthalmic Genet 30:31-36, 2009 13. Sultan I, Wilson MW, Nawaiseh I, et al: Enucleation for retinoblastoma: The experience of a single center in Jordan. Int Ophthalmol 30:407-414, 2010

Guillermo Chantada
Grupo de America Latina de Oncologa Pediatrica; Hospital Juan Pedro Garrahan, Buenos Aires, Argentina

Carlos Leal-Leal
Grupo Mexicano para el Tratamiento del Retinoblastoma; Instituto Nacional de Pediatra, Mexico Distrito Federal, Mexico

Herve Brisse
European Retinoblastoma Imaging Collaboration; Institut Curie, Paris, France

Pim de Graaf
European Retinoblastoma Imaging Collaboration; Vrije Universiteit University Medical Center, Amsterdam, the Netherlands

Rita S. Sitorus
Indonesian Retinoblastoma Protocol; Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Ibrahim Qaddoumi
St Jude Childrens Research Hospital, Memphis, TN

Celia B.G. de Antoneli

Hospital A.C. Camargo, Sao Paolo, Brazil

DOI: 10.1200/JCO.2011.35.9190; published online ahead of print at www.jco.org on July 18, 2011

Does Pre-Enucleation Chemotherapy Lead to Increased Risk of Metastasis in Advanced Retinoblastoma?

TO THE EDITOR: We read the article by Zhao et al1 with interest.
The authors have addressed an important question in an era where chemotherapy has become the mainstay of treatment in advanced retinoblastoma. The ocular salvage rates by chemotherapy in advanced retinoblastoma, International Intraocular Retinoblastoma Classication group D and E eyes, range between 37% and 47%.2-4 The concern about masking of high-risk histopathologic factors is apt especially with the advent of super-selective chemotherapy in retinoblastoma.
3334
2011 by American Society of Clinical Oncology

We understand the limitations posed by a retrospective study. However, we would like to bring to the fore a few issues of concern. First is the lack of a protocol-based treatment in the series presented. The authors have acknowledged that the pre-enucleation chemotherapy regimen was given at doses lower than therapeutic doses previously published. The postenucleation treatment regimen in several patients was not based on pTNM risk and therefore inadequate adjuvant therapy was administered.4 We believe that this decit in treatment may have affected disease-specic survival as an outcome in this study. Second, we beg to differ with the authors in their comment that primary enucleation would have prevented the spread of retinoblastoma in the four patients who developed metastasis. We suspect that extraocular disease may have been present in these patients
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on May 14, 2012. For personal use only. No other uses without permission. Copyright 2011 American Society of Clinical Oncology. All rights reserved.